Republic of the Philippines

NUEVA VIZCAYA STATE UNIVERSITY

Bayombong, Nueva Vizcaya

COLLEGE OF TEACHER EDUCATION

Graduate Program
First Semester, School Year 2017-2018

SEPS 524/SEGS- ADVANCED BIOCHEMISTRY/CHEMISTRY OF LIFE

ARTICLES ON AMINO ACIDS

Submitted by:
MELINDA C. GARPIDA
PhD. Science Education Student

Submitted to:

DAISY V. RIVERA, PhD

Professor
 Article 1
IRON CATALYSTS CAN MODIFY AMINO ACIDS, PEPTIDES TO
CREATE NEW DRUG CANDIDATES

Date: August 1, 2016

Source: University of Illinois at Urbana-Champaign

Summary: For medicinal chemists, making tweaks to peptide structures is key to

developing new drug candidates. Now, researchers have demonstrated that two iron-
containing small-molecule catalysts can help turn certain types of amino acids -- the
building blocks of peptides and proteins -- into an array of potential new forms, even
when part of a larger peptide, while preserving a crucial aspect of their chemistry:
chirality, or "handedness."
Led by Illinois chemistry professor M. Christina White, researchers from the University
of Illinois at Urbana-Champaign in collaboration with researchers at Pfizer Global Research and
Development detailed the new reactivity of the catalysts in the journal Nature.
"This allows us to take one amino acid structure and convert it into many different
structures that represent different functionalities, which could ultimately lead to different
biological and physical properties of the peptide," White said. "It also expands the pool of
unnatural chiral amino acids that are available to researchers to make new structures."
A main advantage to the catalysts, which oxidize bonds between carbon and hydrogen, is
that they preserve the amino acid's sense of chirality. Chiral molecules can have more than one
spatial arrangement of their atoms, or stereochemistry, sometimes known as "right-hand" and
"left-hand" versions. Although they share the same chemical formula, molecules of opposite
handedness can behave very differently in the body. For example, L-DOPA is a drug used to
treat Parkinson's disease, whereas its mirror version, D-DOPA, is biologically inactive.
"That's why having things with defined stereochemistry can be very important for drug
discovery," White said. "It can be that a molecule of one handedness has fantastic physiological
properties, but the same molecule with the opposite handedness could have very detrimental
properties."
Using the two iron catalysts, the researchers were able to take four chiral amino acids --
proline, leucine, valine and norvaline -- and diversify them into 21 different amino acid
structures while preserving their handedness. The new structures can be used to create modified
versions of existing peptides or to build entirely new structures.
Such oxidative amino acid modification is performed routinely in nature to make a
variety of different peptides with different properties. Twenty common amino acids exist in
nature, but are altered by carbon-hydrogen oxidation reactions to change their shape or add
functional groups such as alcohols or carboxylic acids. These reactions are typically catalyzed by
iron-containing enzymes. However, the enzymes are very difficult to work with in a laboratory
setting, White said.
"These enzymes are also very specific. They are usually tailored to one amino acid or one
peptide structure," White said. "Two big advantages to the small-molecule catalysts we've
developed are that they are very general -- they can work on many different amino acid and
peptide structures -- and they are very easy to use. They can create great diversity initiated by
one simple carbon-hydrogen oxidation reaction."
Another major advantage the catalysts have is that, while they are general in what
substrate they can oxidize, they are very specific about which carbon-hydrogen bonds they cut --
so much so that they target a certain spot on amino acids like proline, leucine or valine even
when they are part of a much larger peptide chain. For example, the researchers used the
catalysts to transform a single proline-containing peptide chain into eight different peptides
containing unnatural amino acids.
"This is powerful because right now, if you want to make those eight different peptides,
you would have to do eight different syntheses," White said. "And before you could do that,
you'd have to synthesize the individual unnatural amino acid components. With our method, you
can build one peptide out of bulk chemicals and use one carbon-hydrogen oxidation reaction,
coupled with a reaction to add a functional group, to produce eight new peptides all with retained
handedness."
One of the small-molecule iron catalysts, iron PDP, is available commercially from
Sigma-Aldrich and Strem, and the researchers are in talks to make the second catalyst available
as well.
White's group is working on catalysts that can modify a wider range of amino acids,
particularly those with electron-rich aromatic functionality, which compete with the carbon-
hydrogen bonds for oxidation using the current catalyst.
 ARTICLE 2
GENES’ COMPOSITION GUIDES MORE-OPTIMAL DIETS
Fruit flies and mice grow better and eat less when the amino acid balance of their food
reflects that coded by their exomes.

By Ruth Williams | June 1, 2017

The paper M.D.W. Piper et al., “Matching dietary amino acid balance to the in silico–
translated exome optimizes growth and reproduction without cost to lifespan,” Cell Metabolism,
25:610–21, 2017. Animal studies indicate that while calorie restriction prolongs life, a protein-
rich diet can shorten it, even if overall calories are low. Earlier in life, however, higher protein
consumption is required for reproductive fitness. According to evolutionary theory,
“reproduction and lifespan are locked into a trade-off with each other: you do one well, and do
the other poorly,” says Matthew Piper of Monash University in Melbourne, Australia.
Piper and colleagues had previously found that tinkering with the proportions of certain
amino acids in the diet of fruit flies could somewhat redress this fecundity-longevity imbalance.
And this led Piper to ask if it would be possible to construct a diet that enhances both fecundity
and longevity.
In a moment of inspiration, Piper considered that the recipe for balanced amino acid
consumption might be written in the genes—specifically, in the protein-coding exome. To test
his theory, Piper designed a diet for fruit flies in which the amino acid component precisely
reflected the proportional abundance of each amino acid specified by the insect’s exome. He then
compared the behavior and physiology of flies on this exome-matched diet to those eating diets
that were equivalent in calories and nutrient proportions but not in amino acid ratios.
When given a choice, the flies preferred the exome-matched diet to the unmatched diets.
Interestingly, when allowed to eat ad libitum, flies on the exome-matched diet ate less than those
on the unmatched diets, suggesting the former provided greater satiety and nutritional efficiency.
Flies on the exome-matched diet also exhibited increased growth rate, adult body mass, and
fecundity (egg laying) compared to those on the unmatched diets, while longevity was unaltered.
Similar effects on growth and satiety were seen in mice fed an exome-matched diet.
This is “innovative and important” work, says Andrzej Bartke of Southern Illinois
University. “[It] show[s] that genetic information predicts the utilization of amino acids by an
organism, and that you can therefore design a diet based on the organism’s genes.”
Furthermore, Bartke adds, “most of the fundamental mechanisms linking nutrients to
growth, reproduction, and aging are remarkably similar in widely different species. It is therefore
very reasonable to expect that these findings are relevant to human nutrition.”
That said, Piper hastens to point out that the animals in the study were kept in a
temperature- and humidity-controlled infection-free environment. “What we’re looking into now
is whether [the results are] relevant outside of lab conditions,” he says.
 ARTICLE 3
AN AMINO ACID MYSTERY
LACK OF D-GLUTAMATE IN MOUSE BRAINS HINTS AT UNDISCOVERED ENZYMES
By Louisa Dalton, special to C&EN
Volume 95 Issue 14 | p. 9 | News of The Week
Issue Date: April 3, 2017 | Web Date: March 29, 2017

Right-handed amino acids—found in small doses in nature—are largely a mystery. In

humans, most linger at low concentrations yet play unknown roles in the body. A new survey of
right- and left-handed amino acids in mouse brains thickens the plot. The study’s findings imply
that the brain tightly regulates the levels of right-handed amino acids and that undiscovered
enzymes might flip lefties to righties (ACS Chem. Neurosci. 2017,
DOI: 10.1021/acschemneuro.6b00398).
Ubiquitous left-handed L-amino acids serve as the building blocks of all proteins. The
roles of their right-handed counterparts, D-amino acids, are still not fully understood. In 2000,
scientists figured out that one of them, D-serine, is a neurotransmitter. But, to find the functions
of others, scientists must conduct baseline surveys that determine normal levels of D- and L-
amino acids in various parts of the body, says Daniel W. Armstrong of the University of Texas,
Arlington.
Armstrong’s group collaborated with Adam L. Hartman’s laboratory at Johns Hopkins
University to measure amounts of D- and L-amino acids in the cortices and hippocampi of mice.
The collaborators separated blood from brain tissue and then purified the amino acids in the
samples. They measured them by separating the D and L varieties with chiral high-performance
liquid chromatography.
“Many curious things turned up,” Armstrong says. Levels of most of the 12 D-amino
acids measured were 10 to 2,000 times as high in the brain as in the blood. The concentration of
the neurotransmitter D-serine was among the highest, but D-aspartate and D-glutamine were
even higher. Such quantities suggest many of the D-amino acids play an active role in the brain,
Armstrong says.
Particularly striking was the conspicuous absence of D-glutamate anywhere in the brain
or blood. L-glutamate is the most abundant amino acid in the brain—it is also a neurotransmitter
—so Armstrong expected to see at least some D-glutamate. Yet his team couldn’t detect it at all
with a detection threshold of 0.05 ng per mg of tissue.
The unexpected absence, Armstrong says, implies that the body keeps D-glutamate low for a
physiological reason. It also implies that the brain has a mechanism for efficiently removing D-
glutamate or keeping its levels very low.
Armstrong surmises that undiscovered enzymes may be at work. A known enzyme
converts D- and L-glutamate to D- and L-glutamine, so perhaps a stereoselective enzyme
takes L-glutamine back the other way but doesn’t take D-glutamine, making D-glutamine a sink
for D-glutamate, he says. High brain levels of D-glutamine support that hypothesis, Armstrong
says.
Herman Wolosker of Technion—Israel Institute of Technology notes that for some of the
less abundant amino acids, relatively high fractions exist in the D form. Isoleucine, for instance,
is 24% right-handed in the hippocampus. “It points to the possibility of additional enzymes in the
brain that transform L- into D-amino acids,” he says.